The phenomena leading to the cellular death of the retina and, as a consequence, the loss of visual function are phenomena that occur in processes as varied as ischemias and visible radiation. The chronic development of a state of ischemia in pathologies such as diabetic retinopathy, retinopathy engendered by radiation and damage consecutive to a venous occlusion results in a disturbance of the depolarization of the cellular membrane, which entails, over time, an irreversible destruction of the retina.
Thus, retinal ischemia is observed in the clinic in acute situations such as arterial or venous occlusions of the retina, ocular contusions and also in chronic pathologies such as senile macular degeneration (DMLA), glaucoma, diabetic retinopathy, premature infant retinopathy, and inflammatory diseases and hemopathies that lead to retinal damage even resulting in a number of cases in a total degeneration of the retina. Glaucoma and senile macular degeneration have become the principal causes of poor vision in Western countries, are related to an increase in life expectancy and therefore constitute a real problem for public health.
On account of the frequency and severity of these ocular afflictions there is a real need for an effective treatment for treating and/or preventing diseases associated with retinal ischemia.
In order to counteract damage following a retinal ischemic reperfusion, several pharmacological approaches have been used in experiments. The trappers of free radicals (Celeci et al., 2002; Szabo et al., 2001), the antagonists of glutamate receptors (Lagreze et al., 2001) and adrenergic receptors (Donello et al., 2001; Chao et al., 2001), but also neurotrophic factors (Fontaine et al., 2002; Seigel et al., 2000; Cuevas et al., 1998), calcium channel blockers (Osborne et al., 2002) and inhibitors of the synaptic release of glutamate (Ettaiche et al., 1000) have been proposed as therapeutic agents for the treatment of retinal ischemia. The use of a releaser of glutamate and, more particularly, reluzole in the treatment of retinal ischemia is disclosed in WO 99/42103.
Ischemia induced by an increase of ocular pressure is the model most frequently used for simultaneously studying the mechanisms and potential therapies of retinal ischemia. The degree of the lesion of the retina is a function of the animal species, the duration and the intensity of the ocular pressure imposed. Contrary to the experimental model of retinal ischemia by ligature of the optic nerve, this technique allows, on the one hand, the avoidance of an intraocular hemorrhage consecutive to the beginning of a reperfusion and, on the other hand, offers the advantage of retaining the extraocular structures intact, thus allowing the realizing of local applications of pharmacological substances.
The various pharmacological approaches, validated on experimental animal models, met with two difficulties, namely, on the one hand, the protective, but non-therapeutic aspect of these molecules (with the exception of riluzole) and, on the other hand, their clinical use, which necessitates an administration devoid of any secondary effect on the other organs. The various administration paths used are intravitreous injection and oral, systemic and local paths. The intravitreous injection used for the growth factors can aggravate the inflammatory reaction consecutive to an ischemia but also induce a cellular proliferation at the injection site. The oral path has the problem of the bioavailability of the active principle at the level of the action site, the systemic injection can induce secondary effects on other organs and, finally, the local application can also induce adverse effects on the other ocular tissues, in particular, the loss of corneal sensitivity and a mydriasis.